Myocardial Stiffness in Aging Associated Diastolic Heart Failure

衰老相关舒张性心力衰竭中的心肌僵硬

• 批准号: 7082271
• 负责人: Kenneth S Campbell
• 金额: $ 6.01万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7082271
• 关键词: age difference; aging; animal old age; calcium flux; disease /disorder etiology; heart contraction; heart failure; heart metabolism; hemodynamics; laboratory rat; mature animal; myocardial ischemia /hypoxia; myocardium; myocardium disorder; sarcomeres

DESCRIPTION (provided by applicant): Diastolic dysfunction is the most common cause of congestive heart failure in elderly populations. One year mortality rates for afflicted individuals aged 70 years or older approximate 50%. Therapy options remain empirical. Although very little is known about the etiology of Diastolic Heart Failure (DHF) most studies agree that affected patients exhibit increased ventricular stiffness (reduced chamber compliance). The hypothesis underlying this work is that DHF in elderly populations reflects cross-bridge activity that persists inappropriately during the diastolic (or 'relaxed') phase of the cardiac cycle. These cross-bridges produce an 'active' component of myocardial stiffness that augments the heart's basal (passive) stiffness and impairs ventricular filling by increasing the resistance to inflowing blood. The proposed research will utilize Fischer 344 rats that exhibit aging-associated DHF at 25 months of age. Specific Aim 1 will establish the effects of aging on rat myocardial stiffness. Experiments will test the hypothesis that active stiffness due to inappropriately bound cross-bridges increases to a greater extent with aging than stiffness due to structural components. Intact trabeculae will be isolated from young (5 month) and old (25 month) rats and stretched in the presence and absence of BDM, a cross-bridge inhibitor, to establish the extent of age-dependent changes in active and passive stiffness. Specific Aim 2 will evaluate the effects of altered metabolite concentrations on active stiffness in young and old hearts. Experiments will utilize chemically permeabilized preparations isolated from 5 month and 25 month rat hearts and active stiffness will be assessed by measuring the tension responses to small stretches imposed under sarcomere length control. It is hypothesized that active stiffness due to persistent cross-bridge activity will be enhanced to a greater extent in the old hearts than in the young hearts when the concentrations of hydrogen ions, phosphate ions and ADP are raised to levels mimicking ischemic myocardium. This research is relevant to public health because it investigates the novel hypothesis that aging-related DHF reflects inappropriate contractile activity during the relaxed phase of the cardiac cycle. The experimental results will provide new information about the underlying causes of DHF and should help scientists develop better treatments for diastolic dysfunction in elderly populations.

描述（由申请人提供）：舒张功能障碍是老年人群充血性心力衰竭的最常见原因。 70 岁或以上患者的一年死亡率约为 50%。治疗选择仍然是经验性的。尽管人们对舒张性心力衰竭 (DHF) 的病因知之甚少，但大多数研究都认为受影响的患者表现出心室硬度增加（心室顺应性降低）。这项工作的假设是，老年人群中的 DHF 反映了在心动周期的舒张（或“放松”）阶段不适当地持续存在的跨桥活动。这些跨桥产生心肌僵硬度的“主动”成分，通过增加流入血液的阻力来增强心脏的基础（被动）硬度并损害心室充盈。拟议的研究将利用 Fischer 344 只大鼠，这些大鼠在 25 个月大时表现出与衰老相关的 DHF。具体目标 1 将确定衰老对大鼠心肌僵硬度的影响。实验将检验这样的假设：与结构部件引起的刚度相比，由于不适当地束缚的横桥引起的主动刚度随老化的增加程度更大。从年轻（5 个月）和老年（25 个月）大鼠中分离出完整的小梁，并在存在和不存在 BDM（一种跨桥抑制剂）的情况下进行拉伸，以确定主动和被动刚度随年龄变化的程度。具体目标 2 将评估代谢物浓度改变对年轻和老年心脏主动僵硬度的影响。实验将利用从 5 个月和 25 个月大鼠心脏分离的化学透化制剂，并通过测量在肌节长度控制下施加的小拉伸的张力反应来评估主动硬度。据推测，当氢离子、磷酸根离子和 ADP 的浓度升高到模拟缺血心肌的水平时，老年心脏中由于持续的跨桥活动而导致的主动硬度将比年轻心脏更大程度地增强。这项研究与公共卫生相关，因为它调查了一个新的假设，即与衰老相关的 DHF 反映了心动周期松弛阶段不适当的收缩活动。实验结果将提供有关 DHF 根本原因的新信息，并应帮助科学家开发出更好的治疗老年人舒张功能障碍的方法。